Fibrinolysis Shutdown in COVID-19-Infected Patients Can Result from Iron-Induced Stabilization of Fibril Clots.

Fibrinolysis shutdown in COVID-19 patients recently presented by Wright and colleagues and commented on by Seheult and colleagues unraveled the existence of an unusual mechanism of clot stabilization. Intriguingly, fibrinolysis shutdown is accompanied with markedly elevated D-dimer concentrations, a marker of hyperfibrinolysis. Stable clots persist despite activated fibrinolysis. This paradox can hopefully be explained, given that ferric ions (Fe3+) induce formation of proteolytically insoluble parafibrin. This iron-induced fibrin clot stabilization is mediated by hydroxyl radicals and seems to result from a cross-link of the fibril polymer. Therefore, in cytokine storm, when free iron is available, the regular balance between fibrosis and fibrinolysis is dynamically modulated by iron-mediated continuous catalytic clots stabilization.

Although a role of iron homeostasis (FeH) is underestimated in COVID-19-related research, a “hyperferritinemic syndrome” is already a marker of deregulation of iron homeostasis in patients with COVID-19. If so, a disrupted FeH appears as a core of COVID-19-induced pathology. Cytokine storm is crucial in progression of the COVID-19-initiated pathology. It is accompanied by oxidative stress and erythrocyte destruction obviously, with subsequent dramatical influx of catalytically active iron into damaged tissue. After both local transferrin-binding capacity in physiological fluids and iron-sequestrating capacity of patrolling phagocytes are saturated, an excess of unbound catalytically active iron appears in the lungs. The systemic FeH is tightly regulated. The local FeH disturbance can hardly be monitored by serologic parameters. For this reason, there are just a few reports describing experimentally a deregulation of the local FeH in comparison with systemic FeH. For instance, levels of local hepcidin, a master regulator of FeH, increased in our animal model of the transplanted ascetic tumor in comparison with hepcidin concentrations in blood (T Sukhomlin, PhD, unpublished data, June 2013).

Apparently, the recently published effect of recombinant human erythropoietin administration for treatment of anemic patients infected with COVID-19 indirectly revealed a detrimental role of disrupted local FeH in COVID-19-induced pathology. The recombinant human erythropoietin administration possibly initiated temporal withdrawal of blood transferrin-bound iron for erythropoiesis from iron-overloaded inflamed organs. In addition to successful anticoagulant therapy, removal of an excess of free iron from the injured tissue could be beneficial in treatment of COVID-19 consequences.